Project Summary Idiopathic Pulmonary Fibrosis (IPF) affects approximately 5 million individuals worldwide and responsible for 40,00 deaths in the USA alone. Treatment for IPF is difficult, incomplete, and not curative. Th2-cytokine polarized T cell responses are postulated to mediate inflammation, fibroblast activation, collagen production and progressive fibrosis in IPF, yet there remains a wide knowledge gap on specific molecules involved in the Th2 cytokine-driven immunopathology of IPF. Interleukin-31 (IL-31) is a newly identified cytokine produced by activated Th2 T cells; however, the role of IL-31 in pulmonary inflammation and fibrosis has remained unknown. IL-31 signals exclusively through a heterodimeric receptor complex consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR?). Preliminary data from our laboratory show elevated expression of IL-31, in the mature fibrotic lesions of IPF lungs and mouse model of bleomycin-induced pulmonary fibrosis. Also, key Th-2 cytokines IL-4 and IL-13 directly increased IL-31RA expression in inflamed macrophages and fibroblasts. Importantly, mice deficient in IL-31 signaling show attenuation of fibrosis and improved lung function during bleomycin-induced pulmonary fibrosis. These findings support our central hypothesis that IL-31-driven signaling contributes to the pathological remodelling and lung function decline in IPF. The objective of this application is to identify the role of IL-31 in the immunopathogenesis of IPF using both in vitro and in vivo models. Our long-term goal is to understand how the Th2 cytokines and IL- 31-IL-31RA interactions can be manipulated for preventive and therapeutic purposes in IPF. This hypothesis will be tested by pursuing two specific aims: 1) determine the role of IL-31 in pulmonary fibrosis and lung function decline using genetic models and reciprocal bone marrow cell transfers during bleomycin-induced pulmonary fibrosis; and 2) identify IL-31 producing T cells and characterize IL-31-driven transcriptional networks in IPF. The above aims will establish the role of IL-31 signaling and associated gene networks in pulmonary fibrosis. Further, we will demonstrate that IL-31 is a new target for therapeutic interventions in IPF. The approach is innovative by testing molecular interactions among IL-4, IL-13 and IL-31 and their cross-talk using a mouse model of bleomycin-induced pulmonary fibrosis and knock-out mice. The proposed research is significant, because completion of this study will increase our knowledge of the mechanisms causing IPF and will lead to better medical treatments, cure or prevention.